Recently, the number of patients who need dialysis because of a decrease in renal function tends to increase year by year. The reasons therefor include changes in the living environment, aging and the increase in the number of patients suffering from diabetic nephropathy due to the increase in the number of patients suffering from diabetes mellitus in recent years.
Renal failure is the state wherein excretion of nitrogen metabolites, water and/or electrolytes is insufficient due to blood flow obstruction in kidney, decreased functional nephron and/or obstruction of the urinary tract, leading to incapability to maintain quantitative and qualitative homeostasis of the body fluid. Renal failure includes acute renal failure and chronic renal failure, and both of these show increases in blood urea nitrogen (BUN) and serum creatinine. However, since they show large differences in the speed of progress of the diseased state and in reversibility of the decrease in renal function, they are evidently different diseases. Acute renal failure suddenly occurs and progresses daily (with an increase in the serum creatinine level by not less than 0.5 mg/dL per day as a criterion), but, by removal of its cause, sufficient whole-body control and appropriate conservative treatment or dialysis treatment, recovery of renal function can be basically expected (Non-patent Document 1). On the other hand, establishment of chronic renal failure requires a long period of time. That is, when a renal disease which may cause glomerulonephritis or diabetic nephropathy has gradually progressed year by year resulting in evident increases in BUN and the serum creatinine level, the patient is diagnosed with chronic renal failure. At this time point when the increase in the serum creatinine level is observed, the filtering function for low-molecular waste products, which is the most important function of the kidney, is remarkably decreased; the glomerular filtration rate is not more than 50%; and the decrease in renal function is irreversible. After the establishment of chronic renal failure, renal function gradually decreases for several years, and, when the glomerular filtration rate has decreased to not more than 10%, the chronic renal failure is in the terminal stage, and dialysis or renal transplantation is necessary. Therefore, in therapy of chronic renal failure in the conservative stage, it is important to delay the timing of the transition to dialysis as much as possible (Non-patent Documents 2 and 3).
Examples of the causative diseases of chronic renal failure include nephropathic diseases such as primary renal diseases; renal disorders due to systemic diseases; congenital renal diseases; renal infections; renal disorders due to nephrotoxic substances; and obstructive diseases of the urinary tract. Among these, examples of the major causative diseases include chronic glomerulonephritis, diabetic nephropathy, chronic pyelonephritis, nephrosclerosis and cystic kidney. Especially, the ratios of chronic glomerulonephritis, diabetic nephropathy and nephrosclerosis are high, and, because of the drastic increase in the number of patients suffering from diabetes mellitus in recent years, the ratio of chronic renal failure whose causative disease is diabetic nephropathy has significantly increased.
In chronic renal failure, clinical symptoms such as pulmonary congestion and congestive heart failure due to decreased urine output; neurological and psychotic symptoms due to progress of uremia; anemia due to a decrease in erythropoietin produced in the kidney; and electrolyte imbalances such as hyponatremia and hyperkalemia; as well as digestive symptoms, abnormal bone metabolism and abnormal sugar metabolism, are commonly observed independently of the causative disease of the chronic renal failure.
Further, it is said that chronic renal failure has a common mechanism of progression which is independent of its primary disease. For example, in a commonly used textbook of internal medicine, there is the following description: “In general, in chronic renal failure, progression of chronic renal failure is observed even during a period when the primary disease is suppressed, so that a common mechanism of the decrease in renal function other than the cause of each renal disease is considered to exist.” (Non-patent Document 4).
Further, chronic renal failure is known to show common clinical symptoms even in cases where the causative underlying disease is different. That is, it is said that “Irrespective of whether the disease is primary or secondary, most renal diseases with a chronic process result in an irreversible decrease in renal function after progression of the diseased state, and then become to be called chronic renal failure. This diseased state finally leads to a type of syndrome called uremia, in which the difference depending on the type of the underlying disease is hardly observed and common clinical symptoms appear.” (Non-patent Document 5).
Further, it is said that, in the pathological findings of the kidney, “kidneys of patients suffering from end-stage chronic renal failure show common tissue images in most cases even in cases where the patients have different underlying diseases, and therefore pathological diagnosis of the underlying diseases are often difficult.” (Non-patent Document 6).
Thus, although there are various possible causative diseases of chronic renal failure, it is a characteristic disease distinguishable from the other renal diseases, since it shows characteristic clinical symptoms different from the other renal diseases; it has a common mechanism of progression of the diseased state which is different from that of the primary disease; it shows characteristic findings which do not reflect its causative disease in the pathological findings; and its therapy requires a therapeutic method specific to chronic renal failure.
During the conservative stage before beginning dialysis, therapy of chronic renal failure is based on diet therapies including low protein diets and high-calorie diets, and also includes restriction of salt and water as well as usage of an antihypertensive drug for management of hypertension, which is a risk factor for exacerbation of chronic renal failure. Further, to slow down progression of the diseased state or to ameliorate uremia, oral activated carbon adsorbent preparations may be used in some cases. However, in spite of these therapies, progression of renal failure cannot be well prevented at present, and the number of patients who require hemodialysis because of onset of uremic symptoms due to progression of renal function disorder is consistently increasing. The survival rate of chronic renal failure patients who began dialysis has been improved by virtue of the recent progress in hemodialysis therapy, but there still remain many problems including not only the requirement of 2 to 3 times per week of hospital visit, but also onset of complications of long-term dialysis, infections, increased risks of onset of cardiovascular disturbances, high medical cost and the like. Especially in cases where the patient began dialysis because of diabetic nephropathy, the five-year survival rate is as small as not more than 50% (Non-patent Document 7).
As mentioned above, in chronic renal failure patients, various complications characteristic to chronic renal failure occur. Among these, anemia, which develops and is exacerbated as renal function decreases, is especially problematic. Anemia begins to develop when blood urea nitrogen (BUN) and blood creatinine begin to increase, and almost all the cases of dialysis patients and the like in end-stage renal failure, which then causes hypobulia, easy fatigability, breathlessness, postural vertigo and the like, leading to remarkable decreases in QOL of the patients.
Previously, transfusion was carried out for therapy of anemia due to chronic renal failure, but therapy with a recombinant erythropoietin preparation (rHuEPO preparation) has now become commonly carried out. However, problems such as the fact that therapy with this preparation needs hospital visit and accompanies pain because it is administered subcutaneously, and existence of drug-resistant patients due to occurrence of autoantibody have been pointed out for this therapy. Therefore, a prophylactic or therapeutic agent for anemia due to chronic renal failure, which can be easily administered, whose dosing management can be carried out at home, and whose side effects are small, is demanded.
In recent years, significant involvement of active oxygen in progression of chronic renal failure and exacerbation of complications of chronic renal failure has been pointed out. Superoxide dismutase (this may be hereinafter abbreviated as SOD) is widely distributed in the living bodies of animals, plants, microorganisms and the like, and especially important among the enzymes which decompose superoxide anion radicals (this may be hereinafter abbreviated as O2−) which are highly-reactive active oxygen. In chronic renal failure, the SOD activity contained in the kidney or liver decreases, and the decrease is strongly involved in decreased renal function and onset and exacerbation of complications of chronic renal failure such as cardiovascular disturbances, which are caused by active oxygen (Non-patent Document 8).
In chronic renal failure, low-molecular substances (uremic substances) which accumulate in the living body as renal function decreases cause development of clinical symptoms characteristic to chronic renal failure, which leads to exacerbation of cardiovascular disturbances and a further decrease in renal function. Indoxyl sulphate is a low-molecular substance produced by the process wherein indole produced in the intestine from tryptophan is absorbed into the living body, followed by being metabolized in the liver. Since indoxyl sulphate is excreted mainly from the kidney, efficient excretion is impossible in chronic renal failure because of the decrease in renal function, so that the blood level of indoxyl sulphate increases. Recent interest has focused on indoxyl sulphate as one of the causative substances responsible for exacerbation of various complications of chronic renal failure and exacerbation of cardiovascular disturbances due to endothelial dysfunction (Non-patent Document 9). It is also known that indoxyl sulphate itself is involved in exacerbation of renal disorders (Non-patent Document 10).
Indoxyl sulphate is actively excreted via OAT-3, which is an organic anion transporter existing mainly in the renal tubules, and it is known that OAT-3 decreases in chronic renal failure (Non-patent Document 11).
Further, it is known that the blood levels of various drugs, especially those of the renal excretion type, more easily increase in chronic renal failure compared to healthy individuals. Therefore, in many cases, in chronic renal failure patients, occurrence of side effects of drugs is more frequent and determination of appropriate doses of drugs is difficult. Decreases in drug transporters in the kidney are involved in such phenomena as one of the mechanisms thereof.
Thus, in treatment of chronic renal failure patients, it is important not only to suppress the decrease in the renal function to filtrate low-molecular substances, but also to suppress anemia and the increase in active oxygen caused as complications of the chronic renal failure as much as possible, as well as to prevent the decrease in the transporters which occurs with the renal disorder as much as possible.
Prostaglandin (PG) is a group of naturally-occurring compounds which show various physiological activities, and has the prostanoic acid skeleton in common. The naturally-occurring PGs are grouped, based on the structural features of their five-membered rings, into the PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs, and further grouped into subclasses such as 1, 2 and 3 based on the existence of unsaturation and/or oxidation. Further, their many synthetic analogues are known. PGI2, which is typical among the PGI derivatives, is also called prostacyclin, and known to be a substance having a strong platelet aggregation inhibition action and peripheral vasodilator action.
It is already known that PGI2 and several compounds among the derivatives thereof are effective for disease model animals for glomerulonephritis and diabetic nephropathy, and are clinically effective. However, such findings on PGI2 and derivatives thereof are intended for primary diseases without onset of chronic renal failure. At this stage, renal disorder is evaluated with the urine protein and/or the urinary microalbumin, which increase as the barrier function of the glomerular basement membrane in the kidney to macromolecules is deteriorated. The pharmacological effects are also evaluated based on the decreases in these parameters.
Further, effectiveness of PGI2 derivatives in chronic renal failure has also been reported (Patent Documents 1 to 10, Non-patent Documents 12 to 15). For example, results with m-phenylene PGI2 derivatives including beraprost sodium have been reported, which results were obtained using a model rat subjected to partial nephrectomy and a model rat suffering from chronic renal failure which was prepared by administration of an anti-basement membrane antibody and whose primary disease was nephritis (Patent Document 1 and Non-patent Document 12). For accurate evaluation of renal function in chronic renal failure, glomerular filtration rate (GFR), which is a marker of the renal function to filtrate low-molecular substances, or, as an alternative, eGFR (estimated GFR: estimated glomerular filtration rate) or creatinine clearance is used, and, in addition, the serum creatinine level or BUN, which increases as the renal function to filtrate low-molecular substances decreases, is used. Also in Patent Document 1 and Non-patent Document 12, the serum creatinine level and BUN are used as indices for evaluation of the pharmacological effects. That is, in these rat models, occurrence of chronic renal failure defined with a serum creatinine level and BUN higher than their normal levels was confirmed, followed by beginning administration of a compound of an m-phenylene PGI2 derivative. Thereafter, it was shown that increases of the markers for chronic renal failure, that is, the serum creatinine level and the BUN value, were suppressed compared to those in the control group.
In Patent Document 13, it is described that a PGI2 derivative cicaprost ameliorated microalbuminuria in a canine mild chronic renal failure model, but this evaluation was carried out using the model wherein GFR was maintained at a level of 82% with respect to the normal level, so that the model had not developed chronic renal failure, with which GFR is expected to be not more than 50%. Further, the effect found was merely a decrease in microalbuminuria, which is a reversible change, rather than amelioration of the renal function to filtrate low-molecular substances.
It has been reported that, in chronic renal failure patients, administration of beraprost sodium reduced the rate of decrease in renal function, which is indicated by decrease in the creatinine clearance or in the reciprocal of serum creatinine (Non-patent Literature 14). It is described that a PGI2 derivative treprostinil ameliorated renal function in view of urine production in chronic renal failure patients, but the observation was carried out merely on diuresis, and whether or not chronic renal failure is ameliorated has not been shown (Patent Document 2).
It has been shown that hypoxemia may promote production of erythropoietin via an increased production of renal endogenous PGE2 and PGI2 (Non-patent Document 15). Although the kidney is under hypoxic condition in chronic renal failure and hence productions of endogenous PGE2 and PGI2, as well as erythropoietin, are considered to increase, severe anemia is problematic. The reason for this is not clear, but it is considered that, in renal failure, the ameliorating effect by the mechanism according to this literature may not function sufficiently.
In terms of the ameliorating effect on anemia by PGI2 or a derivative thereof, results showing amelioration of anemia in long-term dialysis patients have been reported only for beraprost sodium (Non-patent Document 16). However, what this literature shows is amelioration of anemia in long-term dialysis patients wherein most kidney cells have lost their intrinsic functions. The amelioration of anemia in a chronic renal failure rat model in the present invention is amelioration of anemia in chronic renal failure in the conservative stage, wherein a part of the cellular functions in the kidney is maintained, so that the diseased state is different from that in the above literature. Thus, the extent of the effect of beraprost sodium in chronic renal failure in the conservative stage cannot be assumed from this literature, and there is no disclosure about this in the literature, so that no remarkable difference in the effect can be assumed among PGI2 derivatives. Further, an ameliorating effect of beraprost sodium on uremia has been reported for chronic renal failure patients. Although anemia is described as one of the particular complications of uremia, there is no description on a particular ameliorating effect of administration of beraprost on anemia (Patent Document 3).
Further, administration of PGI2 or a derivative thereof increases the erythrocytic SOD activity in gastric mucosa of rat and in human systemic sclerosis patients having Raynaud's symptoms (Non-patent Documents 17 and 18), but there is no suggestion at all on whether or not the administration increases the renal SOD activity and whether or not the effect is different among PGI2 and derivatives thereof in chronic renal failure in which the target organ and the disease are totally different. Further, it has not been known that the administration suppresses decreases in renal organic anion transporters in renal failure.
All of cicaprost, m-phenylene PGI2 derivatives, especially beraprost sodium, and further, treprostinil, which are compounds used in the above-mentioned literatures, are PGI2 derivatives produced by improvement of instability of naturally occurring PGI2.
On the other hand, in recent years, PGI2-receptor agonists having a non-prostanoid skeleton have begun to be developed.
It has been pointed out that, among these, compounds represented by the General Formula below:
have the PGI2-receptor agonistic activity and show the antiplatelet action, vasodilator action, bronchodilator action and the like, and that these may be useful for diseases such as transient cerebral ischemic attack, diabetic neuropathy, diabetic gangrene and peripheral circulatory disturbance. Further, in the Examples of this Patent Document, it has been confirmed that the compounds have the antiplatelet action which is an index for the PGI2-receptor agonistic activity. It is described, in this Patent Document, that the compounds represented by the above General Formula are useful as therapeutic agents for glomerulonephritis and diabetic nephropathy, similarly to the other PGI2-receptor agonists (Patent Document 4).
However, there is no description at all on characteristic and remarkable effectiveness of the compounds represented by the above General Formula as therapeutic agents for especially chronic renal failure among renal diseases.
Further, in Patent Documents 5 to 10, it is disclosed that PGI2-receptor agonists having non-prostanoid skeletons can be used for renal failure, but there is no description at all on characteristic and remarkable effectiveness of the agonists as therapeutic agents for chronic renal failure.
That is, there is neither description nor suggestion on the fact that usage of the above compounds as therapeutic agents for chronic renal failure ameliorates the renal function to filtrate low-molecular substances; ameliorates anemia as a significant complication of chronic renal failure; and further, increases the activity of SOD which plays a central role in removal of active oxygen; and/or suppresses decrease in the organic anion transporters responsible for active excretion of uremic substances.
Prior Art References
Patent Documents
Patent Document 1: WO 2000/067748
Patent Document 2: WO 2005/058329
Patent Document 3: WO 2007/007668
Patent Document 4: WO 2002/088084
Patent Document 5: WO 1997/03973
Patent Document 6: WO 1999/21843
Patent Document 7: WO 1999/32435
Patent Document 8: WO 2001/016132
Patent Document 9: WO 2004/034965
Patent Document 10: JP 2000-191523 A
Non-Patent Documents
Non-patent Document 1: Kenjiro Kimura et al. eds., “Lecture Transcript: Renal Medicine, 1st Ed.”, Medical View Co., Ltd., 2004, p. 270, ll. 1 to 10.
Non-patent Document 2: Kenjiro Kimura et al. eds., “Lecture Transcript: Renal Medicine, 1st Ed.”, Medical View Co., Ltd., 2004, pp. 274-275.
Non-patent Document 3: Masaomi Nangaku, Folia Pharmacol Jpn, 118:68-70, 2001.
Non-patent Document 4: “Hyper Reference for Internal Medicine”, Nakayama Shoten Co., Ltd., 1997.
Non-patent Document 5: Kiyoshi Kurokawa ed., “Nephrology—Approach from Pathophysiology”, Nankodo Co., Ltd., 1995, p. 345, left column, ll. 1 to 7.
Non-patent Document 6: Kiyoshi Kurokawa ed., “Nephrology—Approach from Pathophysiology”, Nankodo Co., Ltd., 1995, p. 347, left column, ll. 3 to 5.
Non-patent Document 7: Villar E, et al., J Am Soc Nephrol, 18: 2125-2134. 2007.
Non-patent Document 8: Vaziri N D, et al., Kidney Int, 63: 179-185. 2003.
Non-patent Document 9: Dou L, et al., Kidney Int, 65: 442-451. 2004.
Non-patent Document 10: Enomoto A, et al., Ther Apher Dial, 11 Supple 1: S27-31. 2007.
Non-patent Document 11: Villar S R, et al., Kidney Int, 68: 2704-2713. 2005.
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Non-patent Document 13: Villa E, et al., Am J Hypertens, 6: 253-257. 1993.
Non-patent Document 14: Fujita T, et al., Prostaglandins Leukot Essent Fatty Acids, 65: 223-227. 2001.
Non-patent Document 15: Kiyoshi Kurokawa ed., “Nephrology—Approach from Pathophysiology”, Nankodo Co., Ltd., 1995, pp. 48-49.
Non-patent Document 16: Hidekazu Moriya, Abstract for Meeting of Japanese Society for Dialysis Therapy, O-425, 2006.
Non-patent Document 17: Zsoldos T, et al., Acta Physiol Hung, 64: 325-330. 1984.
Non-patent Document 18: Balbir-Gurman A, et al., Clin Rheumatol, 26: 1517-1521. 2007